Lung cancer is increasingly becoming a disease which occurs in former smokers. Approximately 50% of lung cancers currently happen in former smokers and, as the number of quitters continues to grow (currently 44 million in the U.S.), this will become an increasing health care problem. Strategies must be devised to reduce lung cancer risk in this population through the identification of high risk individuals and the development of effective lung cancer chemoprevention treatments. This proposal will specifically focus on former smokers who have been presumably cured of a prior lung or laryngeal cancer. Patients with a prior smoking-related cancer are expected to have persistent bronchial metaplasia and/or dysplasia, which are precursors for lung cancer, making these individuals ideal candidates for biomarker-integrated chemoprevention trials. Three hundred and thirty-six patients who meet the eligibility criteria will be screened; of these, 80% (2681336) are expected to agree to undergo bronchoscopic biopsies. Approximately 40% (106/268) of these patients are expected to meet the eligibility criteria and be enrolled on this double-blinded, placebo-controlled trial of 13- cis-retinoic acid (13cRA) combined with alpha-tocopherol. With this trial, we will address the following specific aims: Specific Aim 1: To confirm the persistence of premalignant bronchial lesions in former smokers by measuring its incidence and severity. Specific Aim 2: To determine the efficacy of 13cRA and alpha-tocopherol in reversing bronchial metaplasia and/or dysplasia. Specific Aim 3: To measure the toxicity associated with l3cRA and alpha- tocopherol. This proposal will set the framework for Projects 2, 3, and 4, which will examine the subjects of Project 1 for the effects of 13cRA and alpha- tocopherol on the following biomarkers of lung carcinogenesis: mutagen sensitivity and DNA repair capacity (Project 2), markers of genetic instability and phenotypic changes associated with deregulated growth and differentiation (Project 3), and retinoic acid receptors and vitamin A levels in bronchial tissues (Project 4). Our prior studies have shown that 13cRA can reverse oral premalignancy and inhibit second primary tumors in patients with a prior head and neck malignancy. Because studies with high-dose 13cRA have been limited by treatment-related toxicity, this trial will also include alpha-tocopherol, which has been shown to ameliorate 13cRA-related toxicity. Through these efforts, we hope to gain insight into the potential of bronchial metaplasia and dysplasia as markers of increased lung cancer risk and the usefulness of 13cRA combined with alpha-tocopherol as a lung cancer chemoprevention treatment.